Nicotine is considered the gateway drug for other drugs of abuse, since nicotine exposure through cigarette smoking is one of the first drugs routinely self-administered by humans. Multiple factors are positively correlated with the initiation of smoking; one that recently has come to light is in utero exposure to the drug due to maternal smoking. In addition, alcohol rarely is consumed without the concurrent use of cigarettes, especially among women of childbearing age. Nicotine and alcohol each exert profound effects on brain development, resulting in alterations in 1) nicotinic cholinergic receptors, 2) dopaminergic content, receptors, and turnover, and 3) GABAergic functions, all of which are regionally- and gender-specific. The outcomes of such developmental aberrations on dopaminergic mechanisms that subserve addictive behavior are just now being investigated. Yet, the consequences of exposure to both agents have not been studied experimentally, despite strong epidemiological evidence for comorbid effects. Our goal is to identify neuronal mechanism(s) underlying the enhanced nicotine self-administration that we have observed in young adult rat offspring exposed to the combined effects of nicotine and alcohol (EtOH) during brain development. We have developed a non-invasive model for administering both drugs during the critical post-natal period of CNS development, which is the rodent equivalent of the third human trimester and the period of rapid brain growth. This will allow us to examine neuronal alterations resulting from full gestational drug exposure comparable to the human condition. We will characterize the behavioral outcomes of comorbid exposure by studying alterations in acquisition of nicotine self-administration in young adult offspring. Using receptor autoradiography, image analyses, and in vivo microdialysis, we will investigate changes in the dopaminergic and GABAergic cells of the mesocorticolimbic pathway. Since the addictive potential of a drug is correlated with its ability to affect the function(s) of neurons in this pathway, alterations due to gestational exposure to the combined effects of nicotine and EtOH could have profound effects on subsequent drug-taking behavior in the adult offspring.